HLA population genetics.

The HLA system has been extensively studied from an evolutionary perspective. The region contains a number of closely linked genes whose products control a variety of functions concerned with the regulation of immune responses. In addition, the genetic predisposition to over 40 diseases maps to this region. A number of observations indicate that strong selection is acting on the HLA region, including its extensive polymorphism with very even allele frequencies, the preferential occurrence of high levels of variability at positions critical to antigen recognition, the great age of alleles and the patterns of linkage disequilibrium among loci. The form of the selection is unknown. Although balancing selection is a strong candidate, it seems unlikely that only one selective mechanism is operating in this complex multigene family region. Mutation, recombination and gene conversion all contribute to the generation of HLA variability. The apparent great age of many HLA alleles revealed by phylogenetic analysis suggests that the absolute rate of production of new variants is not high. Detailed studies of population and evolutionary features of the HLA region are necessary for an informed discussion of the evolution of disease predisposing genes and epitopes, and of complex multigene families.